Indium fluorozirconate,inzrf7



United States Patent Office US. Cl. 23--51 1 Claim ABSTRACT OF THEDISCLOSURE A new composition of matter, namely, indium fluorozirconate,Il'lZfFq, has been discovered. This compound, when incorporated in oralcompositions for dental caries prophylaxis (e.g., as a constituent of adentifrice, prophylaxis paste, or mouthwash), has demonstratedsubstantial utility as an anti-cariogenic agent.

This invention relates to a new compound indium fluorozirconate, InZrFand to the use of same as an anticariogenic agent in oral compositionsfor caries prophylaxis.

It is commonly recognized that the presence of microquantities offluoride in drinking water (e.-g., 1.0 microgra-m fluoride permilliliter) has a pronounced effect in reducing the incidence of dentalcaries in permanent teeth of children consuming such water from birththrough eight years of age. Fluoride salts have been introduced intopublic water supplies in many communities with good results. This methodof caries prophylaxis is not available, however, to the large numbers ofpeople whose drinking water is obtained from small, privatefluoride-deficient sources such as individual wells, etc. Further, theaddition of fluoride to common public water sources is not alwaysaccepted or permitted.

Topical application of aqueous fluoride solutions by dentists or dentalhygienists provides an excellent measure of protection against dentalcaries. Various fluoride compounds have been employed in this manner,including sodium fluoride, stannous fluoride, and stannousfluorozirconate (SnZrF which is the subject of applicants co-pendingUnited States patent application, Stannous Fluorozirconate andCompositions for Caries Prophylaxis Containing Same, Ser. No. 291,173,filed June 27, 1963. Another method of utilizing the anticariogenicproperties of fluoride salts comprises incorporating such fluoride saltswith a compatible abrasive (such as lava pumice or zirconium silicate)to form a prophylactic paste composition for use by dentists or dentalhygienists in periodic cleaning and polishing of the teeth, as set forthand described in applicants co-pending United States patent application,Prophylactic Dental Paste Compositions Comprising Zirconium Silicate,Ser. No. 314,- 602, filed Oct. 8, 1963.

Limitations on the availability of fluoride therapy by way of watersupplies or professional treatment have led to extensive efforts toincorporate various fluoride salts in oral compositions for use in thehome, most practically obtained in the form of fluoride-containingdentifrices. Again, various fluoride compounds have been employed forthis purpose, especially stannous fluoride.

Although eflective caries protection has been obtained through the useof the aforementioned fluoride compounds in compositions adapted fortopical application 3,440,004 Patented Apr. 22, 1969 to the teeth,occasional side effects have been experienced with certain of the knownanticariogenic agents, particularly certain tin-containing salts. Forexample, a brownish pigmentation of carious lesions has been experiencedafter anticariogenic agents containing the stannous ion have beenapplied to the teeth when the teeth are not properly cleaned with atoothbrush. Although the stain is not necessarily undesirable from aphysiological standpoint, nevertheless, for aesthetic reasons, it wouldbe desirable to provide an effective anticariogenic agent that does notpigment carious enamel.

The utility of certain of the prior art anticariogenic agents has beenlimited by the extent of their solubility in aqueous media. For example,sodium fluoride (NaF) is only soluble to the extent of about 4% inwater. Solubility can, of course, limit the quantity of the anticariogenic ions provided by an agent that are available for reaction with atooth surface. The relative insolubility of certain of the prior artanticariogenic agents limits the value of same for use in prophylacticpaste compositions, since the volume of water in a prophylactic paste isnecessa'rily limited.

Finally, certain of the known prior art anticariogenic agents have beenrelatively unstable in aqueous solution. For example, SnF is subject tooxidation and hydrolysis and, for that reason, must be used in freshlyprepared form or must be used in conjunction with complexing anions inorder to obtain its optimal anticariogenic effect.

For these reasons, and others, dental researchers have continued theirefforts to develop new compositions which are not onlyanticariogenically more effective, but which also exhibit none of thedifliculties associated with certain of the prior art anticariogenicagents.

Accordingly, it is a primary object of the present invention to providea new compound, InZrF which exhibits a high level of anticariogeniceffectiveness and which is non-toxic to living organisms at operableconcentration levels.

It is a related object of the present invention to provide InZrF-containing compositions which are adapted for use in preventivedentistry.

A further object is to provide anticariogenic compositions of matter ofthe character described which can be used at very high concentrationsrelative to known anticariogenic fluoride-containing compounds.

Yet another object of the present invention is to pro vide ananticariogenic agent of the character described which is extremelystable in aqueous solution, even at relatively high concentrations.

' A still further object of the present invention is to provide improvedmethods of reducing the solubility of dental enamel involving theapplication thereto of anticariogenic compositions containing InZrFThese and other objects, advantages, and features of the presentinvention will hereinafter appear, and, for purposes of illustration,but not of limitation, exemplary embodiments of the present inventionare hereinafter described in detail.

In accordance with the present invention, a new composition of matter,indium fluorozirconate, having the formula IHZI'FI], has now beendiscovered. It has further been found that this new compound is highlyeffective as an anticariogenic agent when utilized topically .(i.e.,

in local applications to the teeth) either alone or in combination withother materials, as hereinafter described.

FORMULATION AND CHARACTERISTICS Indium fiuorozirconate (InZrF is a fine,white, crystalline powder. The compound does not melt, but oxidizes intothe respective oxides of Zirconium and indium at about 700 C. At 27 0.,about 50 grams of IHZ1'F7 are soluble per 100 milliliters of distilledwater.

-InZrF may be prepared by co-precipitating InF and ZrF in accordancewith the following example.

Example I 5.06 grams (0.03 mole) of chemical grade indium fluoride (InFwere placed in a polyethylene beaker and 5.0 milliliters of 48.6%hydrofluoric acid (HF) were added and mixed thoroughly therewith. 4.94grams (0.03 mole) of zirconium tetrafluoride (ZrF were placed in aseparate polyethylene beaker, and 5.0 milliliters of 48.6% HP were addedand mixed thoroughly therewith. The contents of each of these beakerswere quantitatively transferred into a third clean polyethylene beakerwith the aid of multiple rinsing with about milliliters of redistilledwater. About milliliters of redistilled water were added to theresulting mixture and the contents stirred until complete solution wasobtained.

The solution was then placed in an oven at 90 C. in order to removeexcess water. The co-precipitate was then collected, rinsed with cold (4C.) 95% ethanol to remove any excess HF, and the resulting whitecrystalline product, InZrF was dried. 9.85 grams (about 0.03 mole) InZrFwere obtained, representing a yield of 98.5%.

Theoretical and actual chemical analyses of a typical product preparedin the foregoing manner are reported in Table 1.

TABLE I.CHEMICAL ANALYSIS Percent Theoretical Percent Actual The lnZrFsalt of the present invention has been characterized according to theconventional Hull-Delaye- Scherrer X-ray diffraction powder technique inorder to produce a film record. Exposure was made using a standard X-raydiffraction camera (diameter 114.6 milliliters) for 4.0 hours at 35 kv.and 18 ma. with a copper target and a nickel filter. As is well known toone skilled in the art, this technique causes all chemical compounds torefract X-rays according to a pattern specific for each compound. TheX-rays expose a film according to a specific pattern, which appears onthe film as characteristic lines, the inter-planar spacing and therelative intensity of each may be measured in order to identify thecompound. Table II records measurements obtained from a film record whenIDZI'F7 was treated as described, and, for comparative purposes,corresponding values obtained with ZrF and InF The values under d arethe inter-planar distances expressed in angstroms, and the values underI represent the relative intensities of the lines obtained byarbitrarily assigning a value of 100 to the most intense line. The datapresented in Table II show that the X-ray diffraction pattern for thenovel lnZrF of the present invention are distinctive and are readilydistinguishable from the patterns of ZrF and InF TABLE II [Powder X-rayDiffraction Patterns of InZrFy, lnFa, and ZrF4] InZrF InF; ZrF

do, A. I/Io do, A I/Io do, A 1/10 10. 77 50 5. 12 100 7. 13 5 6. 4. 577G 6. 46 100 5. 53 50 3. 91 28 4. 44 3 5. 37 80 3. 72 48 3. 98 85 4. 5550 3. 64 22 3. 8G 14 4. 02 30 2. 96 14 3. 48 35 3. 85 100 2. 84 70 3. 303. 81 10 2. 59 5 3. 22 21 3. 46 10 2. 56 10 2. 92 3 3. 30 30 2. 4G 15 2.72 3 2. 87 20 2. 39 5 2. 58 20 2. 81 10 2. 28 28 2. 25 10 2. 67 30 2. 107 2. 10 8 2. 58 10 2. 0O 25 1. 93 18 2. 290 10 1. 96 6 1. 87 2. 14510 1. 90 20 1. 10 1. 996 20 1. 86 8 l. 83 10 1. 928 10 1. 82 7 1. 7410 1. 872 10 1. 81 20 1. 69 5 1. 812 10 1. 79 10 1. 58 5 ANTICARIOGENICEFFECTIVENESS The anticariogenic effectiveness of InZrF', may bedemonstrated by the dental caries experience of rats (standardexperimental animals for anticariogenic studies). The effect of variouscompositions in reducing the solubility of dental enamel in acid is alsoa reliable indicator of anticariogenicity. Enamel solubilitycharacteristics of dental compositions may be determined by a number oftests well known in the art. The particular test for reduction in toothenamel solubility described herein comprises a comparison of acidsolubility of a given tooth after an in vivo treatment with a given testcomposition. The comparison is expressed as ESR, that is, enamelsolubility reduction and the procedure employed is well accepted and hasbeen described .in detail previously (Buttner and Muhler, J. D. Res.,36: 897, 1957).

Rat tooth ESR may be determined in vivo as follows. The teeth of a groupof suitably selected test rats are given single one-minute topicalapplications with solutions of various fluorides, and the animals aresacrified twenty minutes thereafter. Each mandibular hemijaw is removed,the clinical crowns of each are decalcified in 0.2 N (pH 4) sodiumacetate buffer for twenty minutes, and the decalcification solutions areanalyzed for phosphorus by a colorimetric method (Fisk and Subbarow, TheColorimetric Determination of Phosphorus, Jounnal of BiologicalChemistry, 66: 375, 1925). Phosphorus liberation of the teeth topicallytreated with the various fluoride solutions is compared with that ofteeth similarly treated with distilled water control solutions, and theresult of such comparison is reported as a percentage reduction ofenamel solubility (i.e., ESR).

Table III reports percentage reduction values achieved in rat studieswith topically applied solutions of the InZrF salt of the presentinvention and two other fluoride-containing anticariogenic agents, SnFand InF -3H O all at an 8% level. The high degree of anticariogenicityobtained through the use of the lnZrF- compound of the [The Efiect of aSingle Topical Application of Three Different Fluoride Compounds UponEnamel Solubility in the Rat] Treatment pH of ESR Mean, Per- Solutioncent Reduction Distilled Water (Control) 8% SuFz 2. 6 26. 6 8% InFs 3H22. 9 47. 3 8% InZrF1 1. 8 51. 9

As has previously been noted, the II'lZl'Fq salt of the presentinvention is relatively more soluble than certain of the other prior artfluoride-containing anticariogenic agents. For example, the solubilitylimit of NaF in water is reached at about a 4% concentration, hydratedindium fluoride (InF -3H O) is soluble up to about 8.6%, and SnF- issoluble up to about a 30% concentration. However, the lnZrF- salt of thepresent invention is soluble even at a 50% level and may be employedtopically at such elevated level.

ESR data obtained through the use of InZrF', topical solutions atelevated concentrations is given in Table IV. InZrF- solutions at 20%,35%, and 50% concentration levels were applied in the previouslydescribed manner and the 'ESR determination made as also previouslydescribed. The data of Table IV verify that extremely high enamelsolubility reduction figures are achieved with the InZrF- at elevatedconcentrations. However, at concentrations above about the 20% level,the ESR results are approximately equal.

TABLE IV [The Effect of Single Topical Applications of ElevatedConcentrations of InZrF1 Upon Enamel Solubility in the Rat] The effectof aqueous InZrF solutions of different concentrations upon the enamelsolubility of extracted human teeth is reported in Table V. Theprocedure employed has been described previously (Buttner and Muhler, I.D. Res., 37: 412, 1958) and was similar to that involved in thepreviously described in vivo rat ESR studies, with the exception thatthe solution was applied to extracted human teeth. All solutions werefreshly prepared and were employed at their natural pH during a fourminute treatment. The data of Table V verify that extremely high enamelsolubility reductions are achieved through the use of Il'lZI'Fq of thepresent invention.

TABLE V [The Efiect of Different Concentrations of InZrF Upon the EnamelSolubility of Extracted Human Teeth] Treatment Concentration pH MeanPercent (Percent) Reduction 1nZrF7 4. 0 1. 8 89.12 InZrF 8. 0 1. 6 80.62InZ1F1 12. 0 1. 4 88. 60 InZrF1 16. 0 1. 3 88. 40 InZrF1 20.0 1. 0 89.98

about 0.5 of InZrF-,. Prophylactic paste compositions preferablycomprise about 10 to 30% of IIlZI'Fq. Topical solutions incorporatingthe InZrF- of the present invention preferably comprise about 0.012 toabout 50% of the salt, and preferably about 4 to 20% of the salts.

Dentifrice compositions containing Il'lZI'Fq constitute a preferredembodiment of this invention and may contain the usual dentifricecomponents, but preferably, ionically compatible adjuvants are used. Forexample, resinous abrasive materials including particulate condensationprodnets of melamine and urea or formaldehyde and the like which do notform insoluble salts with fluoride ion or inactivate zirconium, indium,and fluoride ions by adsorption can be used to advantage. Otherabrasives which have proven practical in fluoride containing dentifricecompositions and which can be used herein include zirconium silicate,calcium pyrophosphate, insoluble metaphosphates and alumina. Mixtures ofthese abrasives can also be used.

The total amount of abrasive material in dentifrices of this inventioncan range from 0.5% to by weight of the total composition. Preferably,toothpastes contain from 20% to 60% by weight and toothpowders containfrom 60% to 9'5 by weight.

Toothpastes require a binder substance to impart desired textureproperties. Natural gum binders such as gum tragacanth, gum karaya, gumarabic, etc. and seaweed derivatives such as Irish moss and alginates,and water soluble cellulose derivatives, such as hydroxyethyl celluloseand sodium carboxymethyl cellulose can be used for this purpose.Desirably those materials are employed which are most compatible withfluoride ion. Binders which have no ionic groups, such as hydroxyethylcellulose are especially preferred. Improvements in texture can also beattained by including an additional material such as colloidal magnesiumaluminum silicate.

Thickening agents in an amount of from 0.5 to 5.0% by weight can be usedto form a satisfactory toothpaste.

Toothpastes conventionally contain sudsing agents. Suitable sudsingagents include, but are not limited to, water-soluble alkyl sulfateshaving from 8 to 18 carbon atoms in the alkyl radical, such as sodiumlauryl sulfate, water-soluble salts of sulfonated monoglycerides offatty acids having from 10 to 18 carbon atoms in the alkyl radical suchas sodium coconut monoglyceride sulfonate, salts of fatty acid amides oftaurines such as sodium-N-methyl palmitoyl tauride, and salts of fattyacid esters of isethionic acid.

Sudsing agents can be used in the compositions of this invention in anamount of from about 0.5% to about 5.0% by weight of the totalcomposition.

It is also desirable to include some humectant material in a toothpasteto keep it from hardening. Materials commonly used for this purposeinclude glycerine, sorbitol and other polyhydric alcohols. Thehumectants can comprise up to 35% of the toothpaste composition.

Flavoring materials may be included in toothpaste formulations includingsmall amounts of oils of wintergreen and peppermint and sweeteningagents such as saccharin, dextrose and levulose.

The following examples provide exemplary dentifrice formulationscomprising the InZrF- salt of the present invention.

Footnote on following page.

Example II-Continued Constituent: Percent by wt. Potassium H phthalate2.27 Saccharin 0.53 Coloring agents 0.1'6 Flavoring agents 0.82

1 An ammonium salt of a condensation product of NH: and P4010commercially available from the Victor Chemical Company under thetrademark Victamlde, e.g.,

When diluted with water and brushed upon the teeth in the conventionalmanner, this toothpaste markedly reduces the solubility of the dentalenamel.

Example In Constituent: Percent by .wt. Calcium pyrophosphate 39.00lnZrF 0.25 Water 26.32 Glycerine 10.00 Sorbitol (70% aqueous solution)20.00 Sodium coconut monoglyceride sulfonate :80 Sodium coconut alkylsulfate 0.70 Hydroxyethylcellulose 1.50 Magnesium aluminum silicate 0.40Saccharin 0.1 8 Flavoring agents 0.85

This formulation is effective in caries prophylaxis and has good flavor,texture, and foaming characteristics.

As hereinbefore stated, InZrF also exhibits utility as an anticariogenicagent when incorporated with a cleaning and polishing agent (e.g., lavapumice or zirconium silicate) to form a prophylactic paste compositionadapted for application once or twice a year by a dentist or dentalhygienist (or on a self-administered home use basis). Preferredprophylactic pastes embodying zirconium silicate are set forth anddescribed in applicants co-pending United States patent applicationentitled Prophylactic Dental Paste Copositions Comprising ZirconiumSilicate, Ser. No. 314,602, filed Oct. 8, 1963.

Table VI contains representative in vivo rat ESR results obtainedthrough the use of various prophylactic paste compositions. A suitablenumber of test rats were divided into groups and each group was given a15 second prophylaxis with one of the compositions. Twenty minutesfollowing treatment, the animals were sacrificed, and enamelsolubilities were determined in the previously described manner. Thedata of Table VI illustrate the high level of anti-cariogeniceffectiveness obtained with prophylactic paste compositions embodyingthe lnZrF salt of the present invention at several concentrations.

TABLE VI [The Eficet of Single Applications of Various ProphylacticPastcs Upon Enamel Solubility in the Rat] ANIMAL TOXICITY In addition toexhibiting a high level of anticariogenic effectiveness, the InZrF- saltof the present invention may be safely utilized in animal organismswithout any dangerous side effects. The toxicity of lnZrF compares quitefavorably with that of other anticariogenic fluorides, as shown by thefollowing experimental studies.

The toxicity of the InZrF salt has been determined in mice (standardexperimental animals for this purpose), and acute toxicity data aregiven in Table VII. The toxicity is expressed in terms of an LD which isthe lethal dose for 50% of the animals treated.

TABLE VIL-ACUTE TOXICITY Dosage (Mg. F as InZrF /Kg. No. of Percent BodyWt.) Animals Mortality Based on the data of Table VII, it would appearthat the acute LD of InZrF is about 93 mg. fluoride/kilogram bodyweight. In comparison, the acute LD value for sodium fluoride is 36 mg.F/kg. body weight.

lnZrF may be employed in the compositions of this invention even in highconcentration (e.g., as high as about 50%), without producing anyadverse soft tissue reactions. In contrast, prior art fluoride compoundssuch as SnF and SnZrF may not be employed at concentration levelsgreater than about and respectively. InZrF- is completely free of anytissue reaction at any concentration, whereas with SnF even at only an8% level, a mild gingival sloughing is experienced in many instanceswhere tissue inflammation is present at the time of treatment. InZrFstable in aqueous solution for periods of time up to at least days inmarked contrast to the prior art agents containing the easily oxidizedor hydrolyzed stannous ion. Thus, in contrast to such prior artcompounds, InZrF aqueous solutions need not be freshly preparedimmediately prior to use. Moreover, when employed as a topicalanticariogenic agent, InZrF produces no unsightly pigmentation (such asthe brown phosphate pigmentation produced at the site of a cariouslesion when a stannous ion-containing anticariogenic agent is employed).

While the present invention has been described herein with reference tocertain exemplary embodiments thereof, it should be understood thatvarious changes, modifications, and alterations may be effected in thematerials utilized, in the proportions of materials, and in the mannersof formulation without departing from the spirit and the scope of thepresent invention, as defined in the appended claims.

What is claimed is:

1. Indium fiuorozirconate, InZrF References Cited UNITED STATES PATENTS8/1966 Muhler 2351 X OTHER REFERENCES HERBERT T. CARTER, PrimaryExaminer.

US. Cl. X.R. 2388; 167-93

